EP1593392B1 - Vaccin antirabique - Google Patents

Vaccin antirabique Download PDF

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Publication number
EP1593392B1
EP1593392B1 EP04023168A EP04023168A EP1593392B1 EP 1593392 B1 EP1593392 B1 EP 1593392B1 EP 04023168 A EP04023168 A EP 04023168A EP 04023168 A EP04023168 A EP 04023168A EP 1593392 B1 EP1593392 B1 EP 1593392B1
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Prior art keywords
vaccine
rabies
concentration
composition
rabies virus
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German (de)
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EP1593392A1 (fr
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Angelika Dr. Banzhoff
Claudius Dr. Malerczyk
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GSK Vaccines GmbH
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Novartis Vaccines and Diagnostics GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/205—Rhabdoviridae, e.g. rabies virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5252—Virus inactivated (killed)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/20011—Rhabdoviridae
    • C12N2760/20111—Lyssavirus, e.g. rabies virus
    • C12N2760/20134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the invention provides for an immunogenic rabies vaccine comprising a reduced vaccine dose and methods of post-exposure immunization with a reduced dose.
  • the concentration of rabies vaccine antigen per dose is less than 2.5 IU/mL.
  • the concentration of rabies vaccine antigen may be less than half, less than one fourth, or less than one eighth of 2.5 IU/mL.
  • the concentration of rabies vaccine antigen is between 2.4 IU/mL and 0.25 IU/mL, more preferably between 2.0 IU/mL and 1.0 IU/mL and even more preferably between 1.75 IU/mL and 1.25 IU/mL, wherein 1.5 IU/mL is most preferred.
  • the concentration of the rabies virus vaccine antigen in the composition can be 2.2 IU/mL, 1.8 IU/mL, 1.6 IU/mL, 1.4 IU/mL, 1.2 IU/mL, 0.8 IU/mL, 0.6 IU/mL, 0.4 IU/mL, 0.3 IU/mL, or 0.25 IU/mL.
  • the composition is a single-dose unit having a volume of 0.1 mL, the vaccines of the invention are administered intradermally as part of a Thai Red Cross (TRD) or the modified Thai Red Cross regimen.
  • TRC Thai Red Cross ID 2-site
  • PCECV chick embryo cell vaccine
  • rabies virus vaccine antigen concentrations of substantially less than the current WHO recommended 2.5 IU/mL can provide neutralizing antibody titers similar to those generated with the standard dose.
  • the invention provides for a composition comprising a rabies virus vaccine, wherein the concentration of the rabies virus vaccine antigen is less than 2.5 IU/mL.
  • the concentration of the vaccine antigen may be less than half, less than one fourth, or less than one eighth of 2.5 IU/mL.
  • the concentration of the rabies virus vaccine antigen in the composition is preferably less than 1.25 IU/mL, more preferably less than 0.625 IU/mL, and even more preferably less than 0.3125 IU/mL.
  • the concentration of rabies vaccine antigen is between 2.4 IU/mL and 0.25 IU/mL, more preferably between 2.0 IU/mL and 1.0 IU/mL and even more preferably between 1.75 IU/mL and 1.25 IU/mL, wherein 1.5 IU/mL is most preferred.
  • the composition is a single-dose unit having a volume of 0.1 mL.
  • the concentration of the rabies virus vaccine antigen in the composition can be 2.2 IU/mL, 1.8 IU/mL, 1.6 IU/mL, 1.4 IU/mL, 1.2 IU/mL, 0.8 IU/mL, 0.6 IU/mL, 0.4 IU/mL, 0.3 IU/mL, or 0.25 IU/mL.
  • the rabies virus vaccine is produced in a continuous cell line such as a purified chicken embryo cell line, a purified vero cell line, or a human diploid cell line.
  • the vaccines of the invention are given therapeutically as part of a complete post exposure regimen and include administration intradermally.
  • the rabies virus belongs to the family Rhabdoviridae, genus Lyssavirus and comprises an enveloped virion with a single, nonsegmented, negative-stranded RNA.
  • the rabies virus is bullet-shaped with trimers of a the rabies glycoprotein (G) projecting to the exterior of the virus. This G protein is thought to be the major antigen responsible for inducing production of neutralizing antibodies and for conferring immunity against lethal infection with rabies virus.
  • the term "International Units" or "IU” of rabies virus vaccine antigen refers to the international potency concentration measurement used by, for example, the WHO and other international health regulatory agencies (see for example, European Pharmacopoeia, 01/2005:0216, Rabies vaccine for human use prepared in cell cultures,. International Units indicate the predicted potency of a vaccine composition and can be measured using standard assays. For example, the rabies vaccine antigen concentration of a sample inactivated rabies virus vaccine can be calculated using a standard assay to measure the potency of the test vaccine in mouse challenge experiments compared to the potency of a publicly available international reference standard.
  • mice groups of at least ten mice, aged 3 - 4 weeks, are inoculated with single, decreasing doses of vaccine (in accordance with the European Pharmacopoeia) or with two doses, 1 week apart (in accordance with the NIH test).
  • a WHO international standard vaccine is available to compare the titration curve of the test vaccine to that of the IU standard, i.e., to ensure that the PD 50 of the test vaccine is at least equivalent to the IU standard.
  • the PD 50 should lie between the largest and the smallest doses given to the mice;
  • the titration of the challenge virus suspension should show that 0.03 mL of the suspension contained at least 10 LD 50 (the LD 50 should be in the range of 12 - 50 for a valid test);
  • the IU of a rabies vaccine dose may be determined using an antibody binding test (ABBT), which measurement is then converted into IU/mL by comparison with the international standard.
  • ABSBT antibody binding test
  • the rabies inactivated vaccine international standard may be obtained, for example, from the International Laboratory for Biological Standards, Statens Seruminstitute, Copenhagen, Denmark.
  • the vaccines of the invention may be derived from any of the known tissue or cell culture techniques for rabies known in the art, including for example those used with mammalian cells, baculoviruses, bacteria, or yeast. Suitable cell lines may be used to cultivate the rabies virus or to express polynucleotides encoding rabies viral antigens (such as the G protein).
  • the rabies virus is cultivated in cells of mammalian origin.
  • Such cell lines include but are not limited to: human or non-human primate cells (e.g. MRC-5 (ATCC CCL-171), WI-38 (ATCC CCL-75), human embryonic kidney cells (293 cells, typically transformed by sheared adenovirus type 5 DNA), VERO cells from monkey kidneys), horse, cow (e.g. MDBK cells), sheep, dog (e.g. MDCK cells from dog kidneys, ATCC CCL34 MDCK (NBL2) or MDCK 33016, deposit number DSM ACC 2219 as described in WO97/37001 ), cat, and rodent (e.g.
  • human or non-human primate cells e.g. MRC-5 (ATCC CCL-171), WI-38 (ATCC CCL-75), human embryonic kidney cells (293 cells, typically transformed by sheared adenovirus type 5 DNA), VERO cells from monkey kidneys), horse, cow (e.g. MDBK
  • hamster cells such as BHK21-F, HKCC cells, or Chinese hamster ovary cells (CHO cells)
  • BHK21-F HKCC cells
  • CHO cells Chinese hamster ovary cells
  • the cells are immortalized (e.g. PERC.6 cells, as described in WO01/38362 and WO02/40665 , and as deposited under ECACC deposit number 96022940).
  • mammalian cells are utilized, and may be selected from and/or derived from one or more of the following non-limiting cell types: fibroblast cells (e.g. dermal, lung), endothelial cells (e.g. aortic, coronary, pulmonary, vascular, dermal microvascular, umbilical), hepatocytes, keratinocytes, immune cells (e.g. T cell, B cell, macrophage, NK, dendritic), mammary cells (e.g. epithelial), smooth muscle cells (e.g. vascular, aortic, coronary, arterial, uterine, bronchial, cervical, retinal pericytes), melanocytes, neural cells (e.g.
  • fibroblast cells e.g. dermal, lung
  • endothelial cells e.g. aortic, coronary, pulmonary, vascular, dermal microvascular, umbilical
  • hepatocytes e.g. T cell, B cell, macrophage,
  • astrocytes e.g. epithelial, smooth muscle
  • renal cells e.g. epithelial, mesangial, proximal tubule
  • skeletal cells e.g. chondrocyte, osteoclast, osteoblast
  • muscle cells e.g. myoblast, skeletal, smooth, bronchial
  • liver cells retinoblasts, and stromal cells.
  • WO97/37000 and WO97/37001 describe production of animal cells and cell lines that are capable of growth in suspension and in serum free media and are useful in the production and replication of viruses.
  • Preferred rabies virus vaccine cultivation substrates include purified chick embryo cells, purified vero cells, human diploid cells, rhesus diploid cells, hamster kidney cells, and duck embryo cells.
  • Rabies virus vaccines for use in the invention include purified chicken embryo cell vaccines (PCECV) such as Rabipur® (obtainable from Chiron-Behring, Marburg, Germany) and RabAvert® obtainable from Chiron Corp., Emeryville, USA; purified vero cell vaccine (PVRV) such as VerorabTM (obtainable from Aventis Pasteur) and Immovax-Rabies veroTM (obtainable from Aventis Pasteur); chromatographically purified Vero cell culture rabies vaccine (CPRV); human diploid cell vaccine (HDCV) such as Rabivac® (obtainable from from Chiron-Behring, Marburg, Germany); rhesus diploid cell culture vaccine (RVA) such as fetal rhesus monkey lung fibroblast cultures form BioPort; primary Hamster Kidney Cell Culture
  • Preferred rabies virus vaccines for use in the invention include PCECV, PVRV, and HDCV. Processes and means for the production of rabies antigen which make use of these cell lines are described, for example, in “Vaccines”, Plotkin and Orenstein (eds.), 2004, Chapter 37, “Rabies Vaccine”, by Plotkin, Rupprecht, Koprowski.
  • a PCECV inactivated rabies vaccine is prepared by cultivation of the Flury low egg passage (LEP) rabies strain in primary chick embryo fibroblasts (see Example 1).
  • the virus may be cultivated in a synthetic cell culture medium, optionally also including human albumin, polygeline and antibiotics.
  • the virus is then inactivated by approximately 0.025% ⁇ -propiolactone, concentrated and purified by zonal centrifugation in a sucrose density gradient, and lyophlizied. Further discussion of commonly used cell cultures for rabies virus cultivation can be found in Vaccines, Plotkin and Orenstein eds., 4th Ed. 2004, Chapter 37 (pp 1011 - 1038 , see in particular pp 1018 - 1022).
  • the vaccines of the invention may be cultivated in bacterial, insect, or plant cell culture systems.
  • Insect cell expression systems such as baculovirus systems, are known to those of skill in the art and described in, e.g., Summers and Smith, Texas Agricultural Experiment Station Bulletin No. 1555 (1987). Materials and methods for baculovirus/insert cell expression systems are commercially available in kit form from, inter alia, Invitrogen, San Diego CA.
  • Insect cells for use with baculovirus expression vectors include, inter alia, Aedes aegypti, Autographa californica, Bombyx mori, Drosophila melanogaster, Spodoptera frugiperda, and Trichoplusia ni.
  • bacterial and mammalian cell expression systems are also known in the art and described in, e.g., Yeast Genetic Engineering (Barr et al., eds., 1989) Butterworths, London.
  • Bacterial hosts such as E. coli, Bacillus subtilis, and Streptococcus spp., could be used to express constructs encoding rabies viral antigens.
  • Yeast hosts useful in the present invention include, inter alia, Saccharomyces cerevisiae, Candida albicans, Candida maltosa, Hansenual polymorpha, Kluyveromyces fragilis, Kluyveromyces lactis, Pichia guillerimondii, Pichia pastoris, Schizosaccharomyces pombe and Yarrowia lipolytica .
  • Nucleic acid molecules comprising nucleotide sequences of the viral antigens or antibodies of the invention can be stably integrated into a host cell genome or maintained on a stable episomal element in a suitable host cell using various gene delivery techniques well known in the art. See., e.g. , US Patent No. 5,399,346 .
  • the molecules are produced by growing host cells transformed by an expression vector under conditions whereby the protein is expressed.
  • the expressed protein is then isolated from the host cells and purified. If the expression system secretes the protein into growth media, the product can be purified directly from the media. If it is not secreted, it can be isolated from cell lysates.
  • the selection of the appropriate growth conditions and recovery methods are within the skill of the art.
  • the rabies vaccines of the invention preferably comprise inactivated rabies virus cultivated in mammalian cells.
  • General methods of inactivating or killing viruses to destroy their ability to infect mammalian cells are known in the art. Such methods include both chemical and physical means.
  • Chemical means for inactivating a virus include treatment with an effective amount of one or more of the following agents: detergents, formaldehyde, ⁇ -propiolactone, or UV light.
  • Additional chemical means for inactivation include treatment with methylene blue, psoralen, carboxyfullerene (C60) or a combination of any thereof.
  • the rabies vaccines of the invention may comprise further components such as human serum albumin, gelatin, phenolsulfonphthalein, or antibiotics such as neomycin, chlortetracycline, and amphotericin B.
  • the vaccines of the invention may be lyophlilized to a powder form for storage or shipment, and reconstituted in sterile water for immunization.
  • the vaccines of the invention are preferably stored at cool temperatures, preferably 2° to 8° C.
  • the vaccines of the invention may be prepared using one or more concentration techniques such as zonal centrifugation, density gradient centrifugation, ultrafiltration, and chromatography.
  • the invention includes use of reduced concentration rabies virus vaccines in post-exposure dosing regimens by immunization via intradermal administration.
  • the intradermal doses generally comprise a total volume of 0.1 mL.
  • the invention provides for a method of immunizing a subject with a rabies vaccine comprising injecting the subject with one or more doses of rabies vaccine, wherein the concentration of the dose of rabies vaccine antigen is less than 2.5 IU/mL.
  • the concentration of the vaccine antigen may be less than half, less than one fourth, or less than one eighth of 2.5 IU/mL.
  • the concentration of rabies vaccine antigen is between 2.4 IU/mL and 0.25 IU/mL, more preferably between 2.0 IU/mL and 1.0 IU/mL and even more preferably between 1.75 IU/mL and 1.25 IU/mL, wherein 1.5 IU/mL is most preferred.
  • the concentration of the rabies virus vaccine antigen in the composition can be 2.2 IU/mL, 1.8 IU/mL, 1.6 IU/mL, 1.4 IU/mL, 1.2 IU/mL, 0.8 IU/mL, 0.6 IU/mL, 0.4 IU/mL, 0.3 IU/mL, or 0.25 IU/mL.
  • Post-exposure dosing regimens are administered intradermally.
  • Preferred post-exposure rabies vaccines include PCECV, HDCV or RVA vaccines.
  • the invention thus provides for a method of post-exposure immunization against rabies infection comprising immunizing a subject who has been exposed to rabies infection with a rabies vaccine, wherein the concentration of the dose of rabies vaccine antigen is less than 2.5 IU/mL.
  • the concentration of rabies vaccine antigen is between 2.4 IU/mL and 0.25 IU/mL, more preferably between 2.0 IU/mL and 1.0 IU/mL and even more preferably between 1.75 IU/mL and 1.25 IU/mL, wherein 1.5 IU/mL is most preferred.
  • the concentration of the rabies virus vaccine antigen in the composition can be 2.2 IU/mL, 1.8 IU/mL, 1.6 IU/mL, 1.4 IU/mL, 1.2 IU/mL, 0.8 IU/mL, 0.6 IU/mL, 0.4 IU/mL, 0.3 IU/mL, or 0.25 IU/mL.
  • the vaccine is administered in 0.1 mL doses.
  • Intradermal post-exposure dosing regimens for use in the invention include a two site intradermal method known as ("2-2-2-0-1-1"; the numerical abbreviation refers to the numbers of doses administered on days 0,3,7,14,28, and 90; i.e. the number of doses administered on the administration days scheduled in accordance with the standard WHO intramuscular regimen).
  • the "2-2-2-0-1-1" regimen is also known as the Thai Red Cross regimen or TRC-ID.
  • This regimen comprises intradermal administration of 0.1 mL at two sites (such as the upper arm or over each deltoid) at each of days 0, 3 and 7.
  • This regimen further comprises intradermal administration of 0.1 mL at one site (such as the upper arm) on days 28 and 90.
  • TRC-ID A modified version of the TRC-ID is designated ("2-2-2-0-2").
  • This regimen comprises intradermal immunization of 0.1 mL at two sites on days 0, 3, 7 and 28 (with the 90 day booster being omitted).
  • the rabies vaccine according to the invention may be administered after contact with an animal which might be rabid.
  • vaccination should be performed immediately after an animal suspected or confirmed of being rabid (upon contact with a human) caused minor scratches or abrasions without bleeding, single or multiple transdermal bites or scratches, or even after nibbling of uncovered skin.
  • post-exposure treatment can be stopped after a 10 days-observation period in which the animal remains healthy. In these cases, the costs of vaccinating can be considerably reduced by administering the vaccines of the invention.
  • 0.1 mL doses mL at two sites (such as the upper arm or over each deltoid) on days 0, 3 and 7 are sufficient to produce a protective antibody titer of 0.5 IU/mL or more.
  • these doses can have an antigen concentration of about 1.5 IU/mL, 1.0 IU/mL or even 0.5 IU/mL or 0.25 IU/mL.
  • Alternative regimens comprise two 0.1 mL doses on days 0, 5 and 8, or single 0.1 mL doses on days 0, 2, 4, 6 or on days 0, 3, 5, 7.
  • the intradermal dose volume is about 0.1 mL.
  • the rabies virus vaccine antigen concentration per dose in intradermal dosing regimens is consequently less than 2.5 IU/mL (i.e., less than 0.25 IU/0.1mL).
  • the rabies vaccine antigen concentration in an intradermal dosing regimen is less than one half the concentration of 2.5 IU/mL (i.e., less than 0.13 IU/0.1mL), less than one fourth the concentration of 2.5 IU/mL (i.e., less than 0.06 IU/mL), or less than one eighth the concentration of 2.5 IU/mL (i.e., less than 0.03 IU/0.1mL).
  • the reduced dose rabies vaccines of the invention generate neutralizing antibody titers in the subject suitable for meeting international regulatory standards.
  • the vaccines of the invention provide for subject antibody titers greater than 0.5 IU/mL.
  • Measurement of neutralizing antibody titers in rabies vaccine immunized subjects is known in the art and may be accomplished by, for example, the rapid fluorescent focus inhibition test (RFFIT).
  • Post-exposure immunization regimens should be accompanied by administration of rabies immune globulin (RIG).
  • RIG is administered as a single dose of 20 IU per kg of body weight for human RIG or as a single dose of 40 IU per kg of body weight for heterologous (equine) RIG.
  • This single dose of RIG is preferably given at the same time as the first dose of vaccine. If RIG is unavailable at day 0, it may be administered up to day 7.
  • post exposure boost of vaccine given on days 0 and 3 is generally recommended.
  • Such post exposure boosts could be intramuscular or intradermal doses.
  • Subjects suitable for immunization with the vaccines of the invention are humans.
  • a rabies virus antigen for the preparation of a medicament for the treatment of rabies virus infection, wherein the concentration of rabies virus antigen is between 2.4 IU/mL and 0.25 IU/mL, preferably between 2.0 IU/mL and 1.0 IU/mL, more preferably between 1.75 IU/mL and 1.25 IU/mL, and most preferably 1.5 IU/mL.
  • this treatment is a post-exposure treatment.
  • the medicament is administered via intradermal administration.
  • the medicament preferably is to be administered in at least two doses in a period of ten days after contact with the animal.
  • the medicament is to be administered in at least three, four, five, six or seven doses in a period of ten days after after contact with the animal. Usally, the doses have a volume of 0.1 mL.
  • adjuvants are not required to obtain sufficient levels of neutralizing antibody titers, the reduced vaccine doses of the invention may be supplemented with one or more adjuvants.
  • adjuvants for use with the invention include, but are not limited to, one or more of the following set forth below:
  • Mineral containing compositions suitable for use as adjuvants in the invention include mineral salts, such as aluminum salts and calcium salts.
  • the invention includes mineral salts such as hydroxides (e.g. oxyhydroxides), phosphates (e.g. hydroxyphosphates, orthophosphates), sulfates, etc. (e.g. see chapters 8 & 9 of Vaccine Design... (1995) eds. Powell & Newman. ISBN: 030644867X. Plenum .), or mixtures of different mineral compounds (e.g. a mixture of a phosphate and a hydroxide adjuvant, optionally with an excess of the phosphate), with the compounds taking any suitable form (e.g. gel, crystalline, amorphous, etc.), and with adsorption to the salt(s) being preferred.
  • the mineral containing compositions may also be formulated as a particle of metal salt ( WO00/23105 ).
  • Aluminum salts may be included in vaccines of the invention such that the dose of Al 3+ is between 0.2 and 1.0 mg per dose.
  • Oil-emulsion compositions suitable for use as adjuvants in the invention include squalene-water emulsions, such as MF59 (5% Squalene, 0.5% Tween 80, and 0.5% Span 85, formulated into submicron particles using a microfluidizer). See WO90/14837 . See also, Podda, "The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine", Vaccine (2001) 19: 2673-2680 . MF59 is used as the adjuvant in the FLUADTM influenza virus trivalent subunit vaccine.
  • Particularly preferred adjuvants for use in the compositions are submicron oil-in-water emulsions.
  • Preferred submicron oil-in-water emulsions for use herein are squalene/water emulsions optionally containing varying amounts of MTP-PE, such as a submicron oil-in-water emulsion containing 4-5% w/v squalene, 0.25-1.0% w/v Tween 80TM (polyoxyelthylenesorbitan monooleate), and/or 0.25-1.0% Span 85TM (sorbitan trioleate), and, optionally, N-acetylmuramyl-L-alanyl-D-isogluatminyl-L-alanine-2-(1'-2'-dipalmitoyl-sn-glycero-3-huydroxyphosphophoryloxy)-ethylamine (MTP-PE), for example, the submicron oil-in-water e
  • MF59 -- Design and Evaluation of a Safe and Potent Adjuvant for Human Vaccines in Vaccine Design: The Subunit and Adjuvant Approach (Powell, M.F. and Newman, M.J. eds.) Plenum Press, New York, 1995, pp. 277-296 ).
  • MF59 contains 4-5% w/v Squalene (e.g.
  • MTP-PE may be present in an amount of about 0-500 ⁇ g/dose, more preferably 0-250 ⁇ g/dose and most preferably, 0-100 ⁇ g/dose.
  • MF59-0 refers to the above submicron oil-in-water emulsion lacking MTP-PE, while the term MF59-MTP denotes a formulation that contains MTP-PE.
  • MF59-100 contains 100 ⁇ g MTP-PE per dose, and so on.
  • MF69 another submicron oil-in-water emulsion for use herein, contains 4.3% w/v squalene, 0.25% w/v Tween 80TM, and 0.75% w/v Span 85TM and optionally MTP-PE.
  • MF75 also known as SAF, containing 10% squalene, 0.4% Tween 80TM, 5% pluronic-blocked polymer L121, and thr-MDP, also microfluidized into a submicron emulsion.
  • MF75-MTP denotes an MF75 formulation that includes MTP, such as from 100-400 ⁇ g MTP-PE per dose.
  • CFA Complete Freund's adjuvant
  • IFA incomplete Freund's adjuvant
  • Saponin formulations may also be used as adjuvants in the invention.
  • Saponins are a heterologous group of sterol glycosides and triterpenoid glycosides that are found in the bark, leaves, stems, roots and even flowers of a wide range of plant species. Saponin from the bark of the Quillaia saponaria Molina tree have been widely studied as adjuvants. Saponin can also be commercially obtained from Smilax ornata (sarsaprilla), Gypsophilla paniculata (brides veil), and Saponaria officianalis (soap root).
  • Saponin adjuvant formulations include purified formulations, such as QS21, as well as lipid formulations, such as ISCOMs.
  • Saponin compositions have been purified using High Performance Thin Layer Chromatography (HP-LC) and Reversed Phase High Performance Liquid Chromatography (RP-HPLC). Specific purified fractions using these techniques have been identified, including QS7, QS17, QS18, QS21, QH-A, QH-B and QH-C.
  • the saponin is QS21.
  • a method of production of QS21 is disclosed in US Patent No. 5,057,540 .
  • Saponin formulations may also comprise a sterol, such as cholesterol (see WO96/33739 ).
  • ISCOMs Immunostimulating Complexs
  • phospholipid such as phosphatidylethanolamine or phosphatidylcholine.
  • Any known saponin can be used in ISCOMs.
  • the ISCOM includes one or more of Quil A, QHA and QHC.
  • ISCOMS may be devoid of additional detergent. See WO00/07621 .
  • VLPs Virosomes and Virus Like Particles
  • Virosomes and Virus Like Particles can also be used as adjuvants in the invention.
  • These structures generally contain one or more proteins from a virus optionally combined or formulated with a phospholipid. They are generally non-pathogenic, non-replicating and generally do not contain any of the native viral genome. The viral proteins may be recombinantly produced or isolated from whole viruses.
  • viral proteins suitable for use in virosomes or VLPs include proteins derived from influenza virus (such as HA or NA), Hepatitis B virus (such as core or capsid proteins), Hepatitis E virus, measles virus, Sindbis virus, Rotavirus, Foot-and-Mouth Disease virus, Retrovirus, Norwalk virus, human Papilloma virus, HIV, RNA-phages, Q ⁇ -phage (such as coat proteins), GA-phage, fr-phage, AP205 phage, and Ty (such as retrotransposon Ty protein p1).
  • influenza virus such as HA or NA
  • Hepatitis B virus such as core or capsid proteins
  • Hepatitis E virus measles virus
  • Sindbis virus Rotavirus
  • Foot-and-Mouth Disease virus Retrovirus
  • Norwalk virus Norwalk virus
  • human Papilloma virus HIV
  • RNA-phages Q ⁇ -phage (such as coat proteins)
  • GA-phage such as fr-phage
  • VLPs are discussed further in WO03/024480 , WO03/024481 , and Niikura et al., "Chimeric Recombinant Hepatitis E Virus-Like Particles as an Oral Vaccine Vehicle Presenting Foreign Epitopes", Virology (2002) 293:273-280 ; Lenz et al., “Papillomarivurs-Like Particles Induce Acute Activation of Dendritic Cells", Journal of Immunology (2001) 5246-5355 ; Pinto, et al., “Cellular Immune Responses to Human Papillomavirus (HPV)-16 L1 Healthy Volunteers Immunized with Recombinant HPV-16 L1 Virus-Like Particles", Journal of Infectious Diseases (2003) 188:327-338 ; and Gerber et al., "Human Papillomavrisu Virus-Like Particles Are Efficient Oral Immunogens when Coa
  • Immunopotentiating reconstituted influenza virosomes are used as the subunit antigen delivery system in the intranasal trivalent INFLEXALTM product ⁇ Mischler & Metcalfe (2002) Vaccine 20 Suppl 5:B17-23 ⁇ and the INFLUVAC PLUSTM product.
  • Adjuvants suitable for use in the invention include bacterial or microbial derivatives such as:
  • Bioadhesives and mucoadhesives may also be used as adjuvants in the invention.
  • Suitable bioadhesives include esterified hyaluronic acid microspheres ( Singh et al. (2001) J. Cont. Rele. 70:267-276 ) or mucoadhesives such as cross-linked derivatives of poly(acrylic acid), polyvinyl alcohol, polyvinyl pyrollidone, polysaccharides and carboxymethylcellulose. Chitosan and derivatives thereof may also be used as adjuvants in the invention. E.g. WO99/27960 .
  • Microparticles may also be used as adjuvants in the invention.
  • Microparticles i.e. a particle of ⁇ 100nm to ⁇ 150 ⁇ m in diameter, more preferably ⁇ 200nm to ⁇ 30 ⁇ m in diameter, and most preferably ⁇ 500nm to -10pm in diameter
  • materials that are biodegradable and non-toxic e.g. a poly( ⁇ -hydroxy acid), a polyhydroxybutyric acid, a polyorthoester, a polyanhydride, a polycaprolactone, etc.
  • a negatively-charged surface e.g. with SDS
  • a positively-charged surface e.g. with a cationic detergent, such as CTAB
  • liposome formulations suitable for use as adjuvants are described in US Patent No. 6,090,406 , US Patent No. 5,916,588 , and EP 0 626 169 .
  • Adjuvants suitable for use in the invention include polyoxyethylene ethers and polyoxyethylene esters. WO99/52549 . Such formulations further include polyoxyethylene sorbitan ester surfactants in combination with an octoxynol ( WO01/21207 ) as well as polyoxyethylene alkyl ethers or ester surfactants in combination with at least one additional non-ionic surfactant such as an octoxynol ( WO01/21152 ).
  • Preferred polyoxyethylene ethers are selected from the following group: polyoxyethylene-9-lauryl ether (laureth 9), polyoxyethylene-9-steoryl ether, polyoxytheylene-8-steoryl ether, polyoxyethylene-4-lauryl ether, polyoxyethylene-35-lauryl ether, and polyoxyethylene-23-lauryl ether.
  • PCPP J. Polyphosphazene
  • PCPP formulations are described, for example, in Andrianov et al., "Preparation of hydrogel microspheres by coacervation of aqueous polyphophazene solutions", Biomaterials (1998) 19(1-3):109-115 and Payne et al., “Protein Release from Polyphosphazene Matrices", Adv. Drug. Delivery Review (1998) 31(3):185-196 .
  • muramyl peptides suitable for use as adjuvants in the invention include N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-normuramyl-1-alanyl-d-isoglutamine (nor-MDP), and N-acetylmuramyl-1-alanyl-d-isoglutaminyl-1-alanine-2-(1'-2'-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamine MTP-PE).
  • thr-MDP N-acetyl-muramyl-L-threonyl-D-isoglutamine
  • nor-MDP N-acetyl-normuramyl-1-alanyl-d-isoglutamine
  • imidazoquinolone compounds suitable for use adjuvants in the invention include Imiquamod and its homologues, described further in Stanley, “Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential” Clin Exp Dermatol (2002) 27(7):571-577 and Jones, “Resiquimod 3M", Curr Opin Investig Drugs (2003) 4(2):214-218 .
  • the invention may also comprise combinations of aspects of one or more of the adjuvants identified above.
  • adjuvant compositions may be used in the invention:
  • Human immunomodulators suitable for use as adjuvants in the invention include cytokines, such as interleukins (e.g. IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, etc.), interferons (e.g. interferon- ⁇ ), macrophage colony stimulating factor, and tumor necrosis factor.
  • cytokines such as interleukins (e.g. IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, etc.), interferons (e.g. interferon- ⁇ ), macrophage colony stimulating factor, and tumor necrosis factor.
  • Aluminum salts and MF59 are preferred adjuvants for use with injectable influenza vaccines.
  • Bacterial toxins and bioadhesives are preferred adjuvants for use with mucosally-delivered vaccines, such as nasal vaccines.
  • the following example illustrates generation of neutralizing antibodies by administration of low doses of rabies virus vaccine in a Thai Red Cross Indtradermal immunization regimen.
  • HRIG Human Rabies Immunoglobulin
  • the PCECV corresponded to 0.51 IU/ID 0.1 mL dose (undiluted), 0.25/ID 0.1 mL dose (diluted 1:2; this potency corresponds to the minimal potency of 2.5 IU per IM dose recommended by the WHO), 0.125 IU/ID 0.1 mL dose (diluted 1:4), 0.062/ID 0.1 mL dose (diluted 1:8) and 0.031 IU/ID 0.1 mL dose (diluted 1:16).
  • RFFIT rapid fluorescent focus inhibition test
  • the percentage of subjects having an adequate titer of neutralizing antibodies ( ⁇ 0.5 IU/mL) were calculated. On Day 14, as expected, 100% of the subjects receiving undiluted vaccine had titers above 0.5 IU/ml. Also all subjects receiving 1:2 diluted vaccine achieved protective titers. In the 1:4 and 1:8 groups all but one subjects had titers ⁇ 0.5 IU/ml, whereas in the 1:16 group again 100% seroprotection was achieved. Exactly the same seroprotection rates were found on Day 30 with 100% seroprotection in the 1:16 group.

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Claims (10)

  1. Composition destinée à être utilisée dans la vaccination post-exposition d'un sujet humain qui a été exposé à la rage, ladite composition comprenant un vaccin antirabique, dans laquelle la concentration d'antigène viral rabique dans le vaccin est inférieure à 2,5 UI/ml, et dans laquelle la composition est destinée à être administrée par voie intradermique à des doses de 0,1 ml conformément au schéma d'administration de la Croix-Rouge thaïlandaise (2-2-2-0-1-1), dans lequel les abréviations numériques font référence au nombre de doses administrées aux jours 0, 3, 7, 14, 28 et 90 du schéma de vaccination ou selon le schéma d'administration modifié de la Croix-Rouge thaïlandaise (2-2-2-0-2) en omettant le rappel à 90 jours.
  2. Composition destinée à être utilisée selon la revendication 1, dans laquelle la concentration d'antigène viral rabique dans le vaccin est inférieure à la moitié de 2,5 UI/ml.
  3. Composition destinée à être utilisée selon la revendication 2, dans laquelle la concentration d'antigène viral rabique dans le vaccin est inférieure à un quart de 2,5 UI/ml.
  4. Composition destinée à être utilisée selon la revendication 3, dans laquelle la concentration d'antigène viral rabique dans le vaccin est inférieure à un huitième de 2,5 UI/ml.
  5. Composition destinée à être utilisée selon la revendication 1, comprenant un vaccin antirabique, dans laquelle la concentration d'antigène viral rabique dans le vaccin se situe entre 2,4 UI/ml et 0,25 UI/ml.
  6. Composition destinée à être utilisée selon la revendication 5, dans laquelle la concentration d'antigène viral rabique dans le vaccin se situe entre 2,0 UI/ml et 1,0 UI/ml.
  7. Composition destinée à être utilisée selon la revendication 6, dans laquelle la concentration d'antigène viral rabique dans le vaccin se situe entre 1,75 UI/ml et 1,25 UI/ml.
  8. Composition destinée à être utilisée selon la revendication 7, dans laquelle la concentration d'antigène viral rabique dans le vaccin est de 1,5 UI/ml.
  9. Composition destinée à être utilisée selon les revendications 1 à 8, dans laquelle le vaccin antirabique est choisi dans le groupe constitué par du vaccin purifié préparé sur cellules d'embryon de poulet (PCECV), du vaccin purifié préparé sur cellules Vero (PVRV) et du vaccin préparé sur cellules diploïdes humaines (HDCV).
  10. Composition destinée à être utilisée selon les revendications 1 à 9, dans laquelle la vaccination post-exposition s'accompagne d'une administration d'immunoglobuline rabique.
EP04023168A 2004-05-07 2004-09-29 Vaccin antirabique Not-in-force EP1593392B1 (fr)

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GB0514053A GB0514053D0 (en) 2004-09-29 2005-07-07 Rabies vaccine with reduced antigen dose

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US569172P 2004-05-07

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CN1928562B (zh) * 2006-09-22 2011-05-18 中国科学院微生物研究所 一种检测狂犬病病毒的酶联免疫试剂盒
WO2013131984A1 (fr) 2012-03-07 2013-09-12 Novartis Ag Formulations d'immunogènes du virus rabique, pourvues d'un adjuvant
CN106163554B (zh) * 2014-12-23 2021-09-07 依生生物制药(新加坡)私人有限公司 一种包含pika佐剂的狂犬病组合物
CN114917228B (zh) * 2022-06-07 2023-09-26 广西中医药大学 一种用于预防性治疗狂犬病的药方及其制备方法与应用

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